DOCSLIB.ORG

Neurotransmission: Emerging Roles of Endocannabinoids

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Neurotransmission: Emerging Roles of Endocannabinoids View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Dispatch R549 and Keller, L. (2005). Clonal reproduction (2001). Genetic variation in a host- sexes reveals ontogenetic conflict in by males and females in the little fire ant. parasite association: potential for Drosophila. Evolution Int. J. Org. Nature 435, 1230-1234. coevolution and frequency-dependent Evolution 98, 1671–1675. 5. Hamilton, W.D., Axelrod, R., and Tanese, selection. Evolution Int. J. Org. Evolution R. (1990). Sexual reproduction as an 55, 1136–1145. adaptation to resist parasites (A Review). 8. Liersch, S., and Schmid-Hempel, P. Institute of Evolutionary Biology, Proc. Natl. Acad. Sci. USA 87, (1998). Genetic variation within social University of Edinburgh, West Mains 3566–3573. insect colonies reduces parasite load. Road, Edinburgh EH9 3JT, UK. 6. Kondrashov, A.S. (1982). Selection Proc. R. Soc. Lond. B. Biol. Sci. 265, against harmful mutations in large sexual 221–225. E-mail: [email protected] and asexual populations. Genet. Res. 40, 9. Chippendale, A.K., Gibson, J.R., and 325–332. Rice, W.R. (2001). Negative genetic 7. Carius, H.J., Little, T.J., and Ebert, D. correlation for adult fitness between DOI: 10.1016/j.cub.2005.07.001 Neurotransmission: Emerging requires a sustained (5–10 minute) activation of presynaptic CB1 Roles of Endocannabinoids receptors [12,13]. Modulation of synaptic transmission by endocannabinoids Postsynaptic release of endocannabinoids can inhibit presynaptic was initially studied using non- neurotransmitter release on short and long timescales. This retrograde physiological methods, such as inhibition occurs at both excitatory and inhibitory synapses and may seconds-long depolarization or provide a mechanism for synaptic gain control, short-term associative application of high-affinity plasticity, reduction of synaptic crosstalk, and metaplasticity. metabotropic receptor agonists, to evoke endocannabinoid release. Anatol C. Kreitzer [3], which can then diffuse to But the modulatory role of adjacent presynaptic terminals and endocannabinoids during normal Endocannabinoids are a class of suppress neurotransmitter release synaptic activity was not known. lipophilic signaling molecules that for tens of seconds [4,5]. A similar Brenowitz and Regehr [14] found are synthesized and released by phenomenon has been observed that depolarization-evoked postsynaptic neurons in response at excitatory synapses and is endocannabinoid release from to increases in intracellular known as depolarization-induced cerebellar Purkinje cells requires calcium levels or activation of suppression of excitation (DSE) [6]. high levels of intracellular calcium, metabotropic receptors. As their In addition to depolarization- suggesting that depolarization name implies, endocannabinoids mediated calcium entry, activation alone may not play a prominent activate the same G protein- of metabotropic glutamate and role in the release of coupled receptors as the active acetylcholine receptors can drive endocannabinoids under normal compounds in Cannabis sativa endocannabinoid release through physiological conditions. (marijuana). The primary neuronal a separate biosynthetic pathway Another study, in the subtype of this receptor, known as [7,8]. Receptor-mediated cerebellum, by Maejima et al. [7] CB1, is widely distributed in the endocannabinoid production found that 50–100 Hz activation mammalian brain and is expressed requires phospholipase Cβ (PLCβ) of excitatory parallel fiber in presynaptic terminals, where it [9], an enzyme which is activated synapses onto a Purkinje cell can inhibit neurotransmitter by G protein signaling and could yield a transient 10–15% release. The endocannabinoid modulated by calcium. Thus, heterosynaptic inhibition of system is thus well suited for rapid increases in intracellular calcium neurotransmitter release at retrograde signaling across can directly stimulate excitatory climbing fiber activated synapses. Recent endocannabinoid production via synapses on the same Purkinje studies are beginning to elucidate PLD, while at the same time cell. This synaptically evoked the physiological roles of this increasing the efficacy of inhibition was mediated by signalling. receptor-driven PLCβ-mediated endocannabinoids and required Retrograde signaling by biosynthesis. This receptor-driven activation of postsynaptic endocannabinoids was first release is critical for metabotropic glutamate observed in the cerebellum and endocannabinoid-mediated long- receptors, an early indication that hippocampus as a phenomenon term depression (LTD) of receptor-driven endocannabinoid termed depolarization-induced neurotransmitter release at both release is critical under more suppression of inhibition (DSI) [1,2]. excitatory and inhibitory synapses physiological conditions. DSI is a short-term depression of [10–12]. Although LTD can be The first systematic study of neurotransmitter release that can elicited by short (1 second) synaptically evoked be elicited by postsynaptic presynaptic bursts sufficient to endocannabinoid release was that depolarization sufficient to activate activate postsynaptic of Brown et al. [15], again in the voltage-sensitive calcium metabotropic glutamate cerebellum. Following brief trains channels. Increases in intracellular receptors, the subsequent of parallel fiber stimulation, they calcium levels stimulate the receptor-driven endocannabinoid observed a transient ~50% production of endocannabinoids, release may feature slower inhibition of neurotransmitter perhaps via phospholipase D (PLD) kinetics since LTD induction release from parallel fibers, which Current Biology Vol 15 No 14 R550 was mediated by nor climbing fiber stimulation promoting synaptic endocannabinoid release from prior to a parallel fiber burst independence. Purkinje cells. Varying the yields significant While the suppression of frequency of parallel fiber endocannabinoid release. excitatory synapses by stimulation or the number of However, when climbing fiber endocannabinoids provides a stimuli in a train altered the stimulation occurs during or mechanism for limiting synaptic magnitude of this inhibition, which immediately after a parallel fiber excitation, suppression of arose largely from metabotropic burst, a short-term depression of inhibitory synapses may play a glutamate receptor-driven neurotransmitter release is very different role — regulating endocannabinoid release. observed. Thus, Purkinje cell the induction of LTP at nearby Importantly, this retrograde synapses can act as coincidence excitatory synapses. In the signaling was found to be detectors, releasing hippocampus, endocannabinoid- synapse specific — only the endocannabinoids at only those mediated suppression of GABA activated synapses were parallel fiber synapses that are release onto CA1 pyramidal inhibited, whereas other nearby simultaneously active with neurons occurs on both short and synapses were unaffected. climbing fiber firing, giving rise to long timescales. Depolarization of The larger magnitude of a novel form of short-term CA1 pyramidal neurons elicits homosynaptic parallel fiber associative plasticity. DSI, a transient suppression of inhibition relative to A new study by Marcaggi and inhibitory synapses lasting tens of heterosynaptic climbing fiber Attwell [18] provides a different seconds. Carlson et al. [19] found inhibition following high frequency perspective on the physiological that a short excitatory presynaptic parallel fiber stimulation can be role of endocannabinoid signaling. burst, normally ineffective at explained by the different In the studies of synaptically inducing LTP, could elicit LTP if sensitivities of parallel fiber and activated endocannabinoid delivered during DSI. climbing fiber neurotransmitter signaling described above, Similarly, an endocannabinoid- release to presynaptic parallel fiber synapses were mediated LTD of inhibitory modulation, as well as by the stimulated by an electrode placed neurotransmitter release (iLTD) spatial segregation of these in the molecular layer of cerebellar onto CA1 pyramidal neurons [20] synapses on the Purkinje cell cortex. This method yields a also facilitates the induction of dendritic tree. Thus, ‘dense’ pattern of synaptic LTP at nearby excitatory endocannabinoids may play an activation in which nearly all the synapses. Because iLTD is important role in short-term parallel fiber synapses in a synapse-specific and long-lasting, synaptic gain control. If some particular Purkinje cell dendritic the subsequent priming of LTP is excitatory synapses onto a region are active and glutamate also long-lasting and can be postsynaptic cell become very spillover can effectively activate restricted to synapses on a small active, local endocannabinoid perisynaptic metabotropic region of dendrite. release can reduce their strength, glutamate receptors, thereby Endocannabinoids thus play ensuring that a small set of active enhancing endocannabinoid diverse physiological roles in synapses will not control release. But it is not known different cell types and brain postsynaptic firing. whether such dense synapse regions. Their specific role may Although high frequency parallel activation occurs in vivo. vary depending upon temporal fiber trains give rise to retrograde To test whether sparse synaptic and spatial patterns of neuronal inhibition by endocannabinoids, in activation can also elicit activity, regulation of glutamate vivo firing of cerebellar granule
Load more

Recommended publications
  • Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System
    International Journal of Molecular Sciences Review Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System Shenglong Zou and Ujendra Kumar * Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-604-827-3660; Fax: +1-604-822-3035 Received: 9 February 2018; Accepted: 11 March 2018; Published: 13 March 2018 Abstract: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids. Keywords: cannabinoid; endocannabinoid; receptor; signaling; central nervous system 1. Introduction The plant Cannabis sativa, better known as marijuana, has long been used for medical purpose throughout human history.
    [Show full text]
  • NGF-Dependent Retrograde Signaling: Survival Versus Death
    Cell Research (2009) 19:525-526. npg © 2009 IBCB, SIBS, CAS All rights reserved 1001-0602/09 $ 30.00 RESEARCH HIGHLIGHT www.nature.com/cr NGF-dependent retrograde signaling: survival versus death Yang Zhou1, Ting-Jia Lu1, Zhi-Qi Xiong1 1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China Cell Research (2009) 19:525-526. doi: 10.1038/cr.2009.47; published online 4 May 2009 Nerve growth factor (NGF) was which could also provide as the ret- nisms underlying NGF-dependent first discovered more than 5 decades rograde signals [7]. These hypotheses retrograde signaling. Previous studies ago as a molecule that promotes the are not mutually exclusive, and mul- from Campenot’s laboratory demon- survival and maturation of develop- tiple retrograde signals may exist. strated that NGF applied to distal ax- ing neurons in the peripheral nervous In this issue, Mok and colleagues ons of sympathetic neurons supports system [1]. NGF released from target describe a fundamentally different neuronal survival without transport of cells activates tropomyosin-related retrograde mechanism in which NGF NGF towards the cell bodies or TrkA kinase A (TrkA) on axon terminals and suppresses an apoptotic signal in distal phosphorylation in the cell bodies, triggers activation of PI3K/Akt, MEK/ axons [8]. Campenot’s group devel- suggesting that NGF binding to TrkA ERK, and PLCg signaling pathways. oped compartmentalized cultures of in distal axons triggers its downstream The signal then travels retrogradely sympathetic neurons which could seg- signaling cascades locally; afterwards along axon to cell body to promote regate the distal axons from cell bod- the signals travel retrogradely to the neuronal survival [2].
    [Show full text]
  • Endocannabinoid Biosynthesis and Inactivation, from Simple to Complex
    REVIEWS Drug Discovery Today Volume 15, Numbers 11/12 June 2010 Reviews POST SCREEN Endocannabinoid biosynthesis and inactivation, from simple to complex Giulio G. Muccioli Bioanalysis and Pharmacology of Bioactive Lipids Laboratory, CHAM7230, Louvain Drug Research Institute, Universite´ catholique de Louvain, Av. E. Mounier 72, B- 1200 Bruxelles, Belgium Cannabinoid receptors, the primary molecular targets of the endocannabinoid system, are activated by specific bioactive lipids termed ‘endocannabinoids’. These lipid transmitters are synthesized from cell membrane phospholipids through multiple pathways and are inactivated by enzymatic hydrolysis, and their levels are the major parameter driving the endocannabinoid system activity. An in-depth understanding of their metabolic pathways is essential to unravel the endocannabinoid system’s role in physiological and pathological situations and to devise new therapeutic strategies based on the endocannabinoid system. Major advances both in the characterization of anandamide’s and 2- arachidonoylglycerol’s biosynthesis and inactivation pathways and in the discovery of pharmacological tools used to interfere with their metabolism have been made and are discussed in this review. Endocannabinoids are endogenous lipid transmitters that act by persistent activation or blockade and by the lack of tissue speci- binding and activating specific G-protein-coupled-receptors ficity of the ligands developed so far. A novel, more subtle, termed ‘CB1 and CB2 cannabinoid receptors’. To date, N-arachi- approach is the use of allosteric modulators, thus potentially donoylethanolamine (anandamide) and 2-arachidonoylglycerol avoiding some of the aforementioned drawbacks. However, the are the most thoroughly studied endocannabinoids. Anandamide most promising alternative strategy, now supported by a growing is a member of the N-acylethanolamine (NAE) family, a large group number of studies, is to modulate endogenous ligand levels.
    [Show full text]
  • Metabotropic Glutamate Receptors: Intracellular Signaling Pathways Urs Gerber1, Christine E Gee1,2 and Pascal Benquet3
    Metabotropic glutamate receptors: intracellular signaling pathways Urs Gerber1, Christine E Gee1,2 and Pascal Benquet3 Metabotropic glutamate receptors are classified into three mGluRs, will not be discussed explicitly here as this groups, primarily on the basis of sequence similarity and topic is the subject of several comprehensive recent whether they positively couple to the phospholipase C cascade reviews (e.g. see [5]). or negatively couple to adenylyl cyclases. The past decade of research, drawing on sophisticated molecular approaches, has Transduction within the mGluR revealed a multitude of additional intracellular components that Upon binding of glutamate, a conformational change in assemble as protein scaffolds around neuronal metabotropic homodimeric mGluRs promotes the coupling of G pro- glutamate receptors, establishing functional links to teins to specific intracellular domains. Structural studies, postsynaptic density structures, to membrane-bound enzymes beginning with the crystallization and characterization of and ion channels, and to the nucleus. Characterization of these the agonist-bound and ‘unliganded’ forms of the gluta- novel transduction mechanisms is providing new insights into mate binding site of mGluR1, provided initial insights the roles of metabotropic glutamate receptors in the regulation into the underlying process [6]. Agonist binding stabilizes and modulation of diverse functions in the nervous system. the closed conformation of the extracellular domain and Addresses results in G protein activation that is dependent upon a 1 Brain Research Institute, University of Zurich, CH-8057 Zurich, disulfide bridge between conserved cysteine residues in Switzerland the extracellular agonist binding loop and the third trans- 2 Novartis Institutes for Biomedical Research, Novartis Pharma AG, membrane domain [6,7].
    [Show full text]
  • Depletion of Calcium in the Synaptic Cleft of a Calyx-Type Synapse in the Rat Brainstem
    9501 Journal of Physiology (1999), 521.1, pp.123—133 123 Depletion of calcium in the synaptic cleft of a calyx-type synapse in the rat brainstem J. G. G. Borst and B. Sakmann Max-Planck-Institut fur medizinische Forschung, Abteilung Zellphysiologie, Jahnstrasse 29, D_69120 Heidelberg, Germany Appendix by Eberhard von Kitzing (Received 12 April 1999; accepted after revision 23 August 1999) 1. A new form of synaptic depression of excitatory synaptic transmission was observed when making voltage-clamp recordings from large presynaptic terminals, the calyces of Held and postsynaptic cells, the principal cells of the medial nucleus of the trapezoid body (MNTB), in slices of the rat auditory brainstem. 2. A short (100 ms) depolarization of the postsynaptic cell to 0 mV reduced the amplitude of the EPSCs by 35 ± 5 % (n = 7), measured at 10 ms following the depolarization. Recovery occurred within 0·5 s. 3. The reduction of the EPSCs was most probably due to reduced presynaptic calcium influx, since postsynaptic depolarization reduced presynaptic calcium or barium currents. Conversely, presynaptic depolarization also reduced postsynaptic calcium or barium influx, under conditions where transmitter release was minimal. 4. The calcium currents and the postsynaptic depolarization-induced suppression of synaptic transmission recovered with a similar time course, suggesting that this form of synaptic depression was, most probably, due to depletion of Ca¥ in the synaptic cleft. 5. We conclude that when the Ca¥ influx into the pre- or postsynaptic cell is large, extra- cellular Ca¥ is depleted. Under these conditions, the Ca¥ concentration in the synaptic cleft is a sensitive indicator of the level of synaptic activity.
    [Show full text]
  • Alumni Director Cover Page.Pub
    Harvard University Program in Neuroscience History of Enrollment in The Program in Neuroscience July 2018 Updated each July Nicholas Spitzer, M.D./Ph.D. B.A., Harvard College Entered 1966 * Defended May 14, 1969 Advisor: David Poer A Physiological and Histological Invesgaon of the Intercellular Transfer of Small Molecules _____________ Professor of Neurobiology University of California at San Diego Eric Frank, Ph.D. B.A., Reed College Entered 1967 * Defended January 17, 1972 Advisor: Edwin J. Furshpan The Control of Facilitaon at the Neuromuscular Juncon of the Lobster _______________ Professor Emeritus of Physiology Tus University School of Medicine Albert Hudspeth, M.D./Ph.D. B.A., Harvard College Entered 1967 * Defended April 30, 1973 Advisor: David Poer Intercellular Juncons in Epithelia _______________ Professor of Neuroscience The Rockefeller University David Van Essen, Ph.D. B.S., California Instute of Technology Entered 1967 * Defended October 22, 1971 Advisor: John Nicholls Effects of an Electronic Pump on Signaling by Leech Sensory Neurons ______________ Professor of Anatomy and Neurobiology Washington University David Van Essen, Eric Frank, and Albert Hudspeth At the 50th Anniversary celebraon for the creaon of the Harvard Department of Neurobiology October 7, 2016 Richard Mains, Ph.D. Sc.B., M.S., Brown University Entered 1968 * Defended April 24, 1973 Advisor: David Poer Tissue Culture of Dissociated Primary Rat Sympathec Neurons: Studies of Growth, Neurotransmier Metabolism, and Maturaon _______________ Professor of Neuroscience University of Conneccut Health Center Peter MacLeish, Ph.D. B.E.Sc., University of Western Ontario Entered 1969 * Defended December 29, 1976 Advisor: David Poer Synapse Formaon in Cultures of Dissociated Rat Sympathec Neurons Grown on Dissociated Rat Heart Cells _______________ Professor and Director of the Neuroscience Instute Morehouse School of Medicine Peter Sargent, Ph.D.
    [Show full text]
  • A Dissertation Entitled Pituitary Adenylate Cyclase Activating
    A Dissertation entitled Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences __________________________________________ Joseph F. Margiotta, PhD, Committee Chair __________________________________________ David R. Giovanucci, PhD, Committee Member __________________________________________ Scott Molitor, PhD, Committee Member __________________________________________ Joshua Park, PhD, Committee Member __________________________________________ Ruili Xie, PhD, Committee Member __________________________________________ Amanda Byrant-Friedrich, Dr. rer. Nat., Dean College of Graduate Studies The University of Toledo August 2017 i Copyright 2017, Eric R. Starr This document is copyright material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. ii An Abstract of Pituitary Adenylate Cyclase Activating Polypeptide and Synaptic Plasticity at Autonomic Cholinergic Synapses By Eric R. Starr Submitted to the Graduate Faculty as partial fulfillment of the requirements of the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo July 2017 Pituitary adenylate cyclase activating polypeptide (PACAP) is a secretin family neuropeptide, localized to presynaptic terminals throughout the nervous system. In autonomic ciliary ganglion (CG) neurons, PACAP exposure engages
    [Show full text]
  • Role of Endogenous Cannabinoids in Synaptic Signaling
    Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003. Role of Endogenous Cannabinoids in Synaptic Signaling TAMAS´ F. FREUND, ISTVAN´ KATONA, AND DANIELE PIOMELLI Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Germany; and Department of Pharmacology, University of California Irvine, Irvine, California I. Introduction 1018 II. The Life Cycle of Endocannabinoids 1020 A. Introduction 1020 B. Biosynthetic pathways 1020 C. Termination of endocannabinoid effects: transport and degradation 1023 III. Regional and Cellular Distribution of Neuronal CB1 Cannabinoid Receptors 1028 A. Characteristic differences in CB1 receptor distribution in the brain 1028 B. Selective expression of CB1 cannabinoid receptors by identified cell types of complex networks 1030 IV. Anatomical, Physiological, and Pharmacological Evidence for the Presynaptic Localization of CB1 Cannabinoid Receptors in the Brain 1035 A. Anatomical evidence for presynaptic cannabinoid receptors 1036 B. Physiological and pharmacological evidence for presynaptic cannabinoid receptors 1039 C. Are there postsynaptic CB1 receptors? 1044 V. Physiological Roles of Endocannabinoids 1045 A. The cannabinoid root 1045 B. The DSI (DSE) root: control of GABAergic and glutamatergic synaptic transmission via retrograde synaptic signaling 1048 C. Marriage of the two lines of research explains the mechanism of DSI (and DSE) while endowing endocannabinoids with function 1049 D. Electrical activity patterns required for the release of endocannabinoids 1054 VI. Conclusions 1056 Freund, Tama´s F., Istva´n Katona, and Daniele Piomelli. Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003.—Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimi- metic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors.
    [Show full text]
  • Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions
    10230 • The Journal of Neuroscience, October 5, 2016 • 36(40):10230–10238 Viewpoints Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions X Natalie E. Zlebnik1 and XJoseph F. Cheer1,2 Departments of 1Anatomy and Neurobiology and 2Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201 The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward- related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotrans- mitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability. Key words: addiction; cocaine; drugs of abuse; endocannabinoid; nucleus accumbens; plasticity; reward; THC; ventral tegmental nucleus Introduction Overview of the eCB system Emerging work has identified endocannabinoid (eCB) signaling The eCB system encompasses several G-protein-coupled recep- as an important mediator of synaptic plasticity in mesocortico- tors (GPCRs) and lipid signaling molecules as well as their limbic and corticostriatal pathways involved in the control of biosynthetic and metabolic machinery.
    [Show full text]
  • Communication Networks in the Brain
    Communication Networks in the Brain Neurons, Receptors, Neurotransmitters, and Alcohol David M. Lovinger, Ph.D. Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neuron’s specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors exist—ligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-protein–coupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication,
    [Show full text]
  • Retrograde Signaling at Central Synapses
    Colloquium Retrograde signaling at central synapses Huizhong W. Tao and Mu-ming Poo* Department of Molecular and Cellular Biology, University of California, Berkeley, CA 97420 Transcellular retrograde signaling from the postsynaptic target cell mation processing and storage in the brain, the central synapse to the presynaptic neuron plays critical roles in the formation, must be formed and regulated under appropriate control. Syn- maturation, and plasticity of synaptic connections. We here review apses are formed only between specific pre- and postsynaptic recent progress in our understanding of the retrograde signaling at partners and stabilized at specific locations on the dendrite. developing central synapses. Three forms of potential retrograde Synapse formation is accompanied by a coordinated develop- signals—membrane-permeant factors, membrane-bound factors, ment of pre- and postsynaptic molecular and structural special- and secreted factors—have been implicated at both developing izations, which requires exchanges of information between pre- and mature synapses. Although many of these signals may be and postsynaptic cells at all stages of synapse development, via active constitutively, retrograde factors produced in association anterograde as well as retrograde signaling. with activity-dependent synaptic plasticity, e.g., long-term poten- tiation and long-term depression, are of particular interest, be- (i) Signaling Before Synaptic Contact. After long-range axon path- cause they may induce modification of neuronal excitability and finding, growth cones approach their target cell, and the process synaptic transmission, functions directly related to the processing of synapse formation begins. It is likely that navigation of the and storage of information in the nervous system. growth cone is stalled and axon differentiation begins in re- sponse to factors secreted from the target cell.
    [Show full text]
  • Editorial: Homeostatic and Retrograde Signaling Mechanisms Modulating Presynaptic Function and Plasticity
    Editorial: Homeostatic and retrograde signaling mechanisms modulating presynaptic function and plasticity The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Subramanian, Jaichandar, and Dion Dickman. “Editorial: Homeostatic and Retrograde Signaling Mechanisms Modulating Presynaptic Function and Plasticity.” Front. Cell. Neurosci. 9 (September 30, 2015). As Published http://dx.doi.org/10.3389/fncel.2015.00380 Publisher Frontiers Research Foundation Version Final published version Citable link http://hdl.handle.net/1721.1/99678 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/4.0/ EDITORIAL published: 30 September 2015 doi: 10.3389/fncel.2015.00380 Editorial: Homeostatic and retrograde signaling mechanisms modulating presynaptic function and plasticity Jaichandar Subramanian 1* and Dion Dickman 2 1 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA, 2 Department of Neurobiology, University of Southern California, Los Angeles, CA, USA Keywords: homeostatic plasticity, presynaptic adaptation, retrograde signaling, neurotransmitter release, neurological disease Dynamic reorganization of neural circuits can occur through the selective strengthening of synapses between neurons that are coactive in response to the encoded information (Shatz, 1990). However, the positive feedback resulting from synaptic strengthening and neuronal coactivity can lead to the destabilization of neuronal networks. Thus, synapses must maintain the capacity for change necessary for learning and memory, yet constrain this inherently destabilizing flexibility to enable stable neural function throughout life. Evidence has emerged in recent years that activity within neural circuits can shape the synaptic properties of component neurons in a manner that maintains stable excitatory drive, a process referred to as homeostatic synaptic plasticity (Turrigiano and Nelson, 2000; Pozo and Goda, 2010; Davis, 2013).
    [Show full text]